Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

Abstract

Previous genome-wide association studies (GWAS) of HIV-1–infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5Δ32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation—mostly in the HLA and CCR5 regions—explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.

Association of a 3′ untranslated region polymorphism in proprotein convertase subtilisin/kexin type 9 with HIV viral load and CD4+ levels in HIV/hepatitis C virus coinfected women

“…There is little global variation in rs17111557 except in African ancestry populations - for example, in the CEU (Utah Residents with Northern and Western European Ancestry) HapMap population allele frequencies at this locus are 99% C and 1% T. Many if not all genetic studies of HIV have been conducted in European ancestry cohorts [10, 11] .…”

“…Only two genetic regions have consistent associations with HIV pathogenesis in genome-wide association studies (GWAS) – the human leukocyte antigen (HLA) class I region and the chemokine (C-C motif) receptor 5 (CCR5) region [10] . GWAS can be underpowered to identify associations with moderate effect sizes.…”

“…GWAS can be underpowered to identify associations with moderate effect sizes. GWAS of HIV are additionally limited by small sample sizes (compared to general population samples) and by heavy reliance on European ancestry cohorts [10] , although there are exceptions [11] . Thus, there remains a place in HIV research for candidate gene studies where a strong rationale exists for interrogation of certain genes, as is the case for genes that regulate cellular cholesterol levels.…”

RICH2 is implicated in viraemic control of HIV-1 in black South African individuals

“…The large variability in HIV-1 control has been attributed to: host genes variability, viral pathogenicity and environmental factors (Fellay et al, 2009). In a recent genome wide association study (GWAS), up to 25% of the variability in viral load was attributed to common genetic variations in the Human Leukocyte Antigen (HLA) and CCR5-encoding regions of the genome (McLaren et al, 2015). Many individuals that control infection however do not possess these well described host gene variants.…”

Replication Capacity of Viruses from Acute Infection Drives HIV-1 Disease Progression

“…The stabilized VL reached after acute infection, referred to as the VL set point, is often used as a marker of disease progression, as it is associated with time to AIDS (5). However, genome-wide association studies estimate that host factors account for only 15 to 25% of the variation in set point VL (6,7), and several studies have implied a role for viral factors. In transmission pairs, a strong correlation has been observed between the VLs of the donor and the recipient (8)(9)(10)(11)(12), demonstrating that the VL set point is at least partially heritable.…”